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Cell Adhesion Flashcards

1
Q

Why is adhesion to the ECM important?

A 
Anchorage dependent growth
Suppresses apoptosis
Regulates gene. Expression
Organisation of tissues
Angiogenesis
Wound healing and clotting
Migration
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2
Q

What are focal adhesions

A

Connect cell to ECM

Integrins- link ECM to the actin cytoskeleton

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3
Q

4 major families of cell adhesion

A

Homophillic
Cadherins (e-cadherins)
Igs (NCAM)

Heterophillic
Integrins (avb3)
Selectins (p-selectin)o

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4
Q

Function of Integrins in epithelial cells

A

Connect the basal laminate to intermediate filaments, hemidesmosomes
Integrins a6B4, the B4 subunit is larger allowing it to connect to intermediate filaments

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5
Q

Function of Integrins in non epithelial cells

A

Integrins adhesome
Focal adhesions, focal complexes and podosomes
Connects the actin cytoskeleton to the ECM
Binds to RGD in fibronectin
190 adapter proteins,

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6
Q

Ways to visualise focal adhesions

A

GFP stained proteins e.g. Actin and paxillin

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7
Q

Integrin inside out signalling

A

Ab heterodimers
A has 4-5 extra cellular domains, B has 7
Movements near BA domain and propeller increase affinity
Separation of the cytoplasmic and transmembrane
A domains usually have ca or mg in one cation site, the other two sits are occupied by the acidic residues in the RGD sequence of the ligand

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8
Q

Structural adaptors

A

Talin, filamin and tension

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9
Q

Scaffolding adaptors

A

Paxillin kindlin Integrin-linked kinase, src

Used to propagate the signal transduction

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10
Q

Nanodiscs

A

Model membranes that resemble HDL particles
Small lipid bilayer patch with a membrane scaffold protein to shield from water
Has shown that talon binding is insufficient to activate
May also require kindlin activation

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11
Q

ECM and Integrins binding regions

How do pathogens use this?

A

Ligands such as fibronectin have an RGD loop that Integrins bind within the third repeat
Some viruses have an RGD on the surface to trick the cells into latching onto them

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12
Q

Activation of Integrins by glycoproteins

A

Glycoproteins Ia/IIa bind to exposed collagen

Outside in signal that leads to Integrins activation

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13
Q

The B3 Integrins
Where found
Disease

A

aIIbB3 Integrins found on platelets
Fibrinogen binds one Integrins receptor at each end which allows it to link platelets together

Glanzmanns disease- genetically deficient in B3 bleed excessively

RGD containing peptides can be used as antithromibics during surgery

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14
Q

Cdc42 pathway

A

Par6 -> polarity

WASP -> Arp2/3 -> filo podia

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15
Q

Rac pathway

A

WAVE
Arp2/3
Lamellipodia

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16
Q

Rho pathway

A

Activated by LPA
Rho kinase -> myosin LC pi -> myosin activity -> stress fibre
Formin -> actin polymerisation

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17
Q

PI3K AKT pathway

A

Phoshorylates lipids -> PIP3
PIP3 recruits the Ser/thr kinase AKT to the membrane
AKT inhibits transcription factors for cell death and can phosphorylase remodelling proteins

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18
Q

Rad Rho cdc42 and Integrins

A

Adaptors proteins of Integrins e.g. Paxillin and focal adhesions kinase can phosphorylase cdc42 etc to give focal adhesions turnover
Arp2/3 allows actin branching

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19
Q

ERK + c-Jun

A

FAK, Src and Ras activate MAPK

Increases transcription of c-Jun to promote cell cycle

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20
Q

ERK and Jnk

A

Jnk regulates c-Jun (cell cycle promoter)

CAS and crk regulate jnk

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21
Q

ECM stiffness and Integrins

A

Integrins clustering causes FAK (p) to act on B-catenin
B-catenin promote transcription of MYC
MYC signals miR-18a to stop BRCA1 and PTEN
PTEN stops migration and invasion
ECM stiffness promotes cancer

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22
Q

Integrins and calcium

A

Ca binds to the MIDAS and LIMBS sites and reinforces the bent active state
Activated in the presence of Mn

23
Q

Integrins activation by talin

A

Talin binds to the B3 subunit
F727 of B3 embeds in the talin S1-S2 loop
Inter membrane salt bridge clasp loosens
K320 energetically compensates
Talin recruits vinculin to stabilise complex

24
Q

Inter membrane clasps

A

Inter and outer membrane clasps hold the 2integrin tail segments together

25
Knockout mice to study Integrins isoforms
18a and 8b Integrins -> 24 Integrins B1- inner cell mass day 5 A4- heart defect day 12 A5- abnormal mesoderm day 9
26
Signalling hubs
Groups of the Integrins adhesome 1-20 groups according to biological activity Connectivity makes it robust to failures When proteins with 16+ interactions removed it is still intact 30+ proteins such as Integrins, paxillin, FAK = embryonic lethal EXCEPTION- Src is most connected but only osteopetrosis, support by other family members
27
Adhesion and disease
Of 232 adhesome genes, 22% caused specific disease In the total genome, 11% are linked Muscle and heart diseases because of the stress in these tissues Haematological- cytoskeleton in RBCs Dermatological- need for adhesion for barrier
28
Antibodies to measure Integrins activation
B subunit has 4 EGF like repeats Unfolding exposes I-EGF-1 Exposes the epitope for antibody KIM127
29
Myotendinous junction
Primary site of force Transmission from muscle proteins to tendon Integrins link muscle cells via ECM Also link tendon cells to ECM
30
Testing talin mutants
Contains 2541 amino acids Replaced wild type talin with rescue transgenes E1770A needed for autoinhibition, stops R9 and F3 folding together Rod domain at 1655-1822 is amphipathic 5 helix Tyr377 docks into bundle, basic loop interacts with acidic residues in helix 4 R3 has destabilising Thr residues- removal stabilises the domain and lowers vinculin binding
31
Integrins activation in blood clotting
``` Main binds to par1 Creates IP3 + DAG IP3 binds to ca channels PKC and CALDEG-GEFI acts as GEF for Rap1 Rap binds RIAM recruits to membrane RIAM binds talin PIPK creates acidic surface for basic talin to stick to membrane Talin switched off when phosphorylated ```
32
Talin phosphorylation
Talin recognises NPxY in Integrins tail T144/T150 phosphorylation in the F1 loop can disrupt membrane association Reduces + charge, stops loop from forming helix
33
Cross talk blood clotting and GPCRs
Many GPCRs activate PLCB IP3 -> InsP3R DAG + Ca -> CALDAG-GEFI Many GPCRs could give outside in signalling
34
GTPase signalling cycle
GEF- changes GDP for GTP GAP- hydrolysis GTP Cross talk- GAPs and GEFs can be created by other signalling pathways
35
RIAM and talin activation
``` PIPK convert PI -> PIP -> PIP2 PLC converts PIP2 -> DAG and IP3 RIAM only binds folded talin PIP2 in membrane stops autoinhibition Out competes the R9 domain for the F3 domain ```
36
RIAM and vinculin
Talin R2-R3 binds RIAM in unfolded Vinculin binds R3 in unfolded Unfolding disrupts RIAM and link to rap1 Allows vinculin to bind to actin and talin When talin is stretched by actin, vinculin allows stabilisation
37
Mechanobiology Mechanosensing Mechanotransduction
Forces contribute to cells and tissues Sensing- protein conformation altered Transduction- elicit cellular response proportional to stimuli
38
Forces that act on cells | Affect of stress on a cell
Stiffer ECM will incur more force -> B catenin Nucleus changes genes in response to force, B catenin -> miRNA -> PTEN repressor -> tumour Shear stress of a cell moving
39
Stretching a talin molecule
Link from R1 to plate surface Magnetic bead attached to R3 Jumps as each domain unfolds Allows experiments in the presence of force When unfolded to a random coil state, vinculin dissociates
40
Vinculin locks talin in the active state | Vinculin is biphasic
At 5pN R3 unfolds, switches RIAM for vinculin Changes nascent adhesions to focal adhesions Inhibited by - less than 5pN when RIAM dominated >25pN as this is random coil
41
Mechanise siting transcription factors
YAP/TAZ recruited TEAD transcription factors Transcription of proliferation genes Explains why a stiffer matrix causes cancer
42
Measuring forces in live cells
Pillar arrays- measure displacement of pillar Magnetic tweezers- movement of magnet/bead Optical trap- measures movement of point by diffraction
43
What are cadherins | Structure
Several PTMs - glycosylation, phosphorylation, cleavage 720-750 AAs 3-5 extra cellular repeats Repeats 1-3 have a Ca binding site N-terminus has HAV sequence for ligand binding Cytoplasmic c terminal has LSSL that binds beta catenin
44
Cadherins subclasses | Cadherins binding
E, P, N only bind to same type Tryptophan docking between cadherins Needs calcium to strengthen flexible hinge region
45
Cadherins experiment to show in adhesive junctions
GFP tagged cadherins Or transferred cadherins into leukocytes Upon calcium addition, epithelial layer started to form Embryo compaction- 8 cell stage compaction is seen
46
The types of cadherins in development
E cadherins- preimplantation, epithelial tissue P cadherins- trophoblast N-cadherins - nervous system, cardiac and skeletal Cells also segregate into different levels of cadherins Cells may express different subclasses Block of EP cadherins then the blastula becomes disorganised
47
Cadherins at adherens junctions
Tail of cadherins link to B catenin B catenin links to a catenin to F actin and vinculin Alpha actin in cross links actin filaments Vinculin VASP complexes can create focal adhesion bundles PIP2 activates vinculin
48
Cadherins experiments under force
Cadherins catenin complex only under force Need force to activate actin binding Stretching of alpha actinin exposes vinculin binding sites which stabilises the focal adhesion
49
B catenin moonlighting in Wnt signalling
Wnt -> frizzled, associates with LRP cofactor GSK3 phosphorylated LRP to bind axin Means that CK1 and GSK3 can't phosphorylated b catenin Translocation to nucleus B catenin binds to TCF and displaces Gro repressor Recruits pygo, LGS Activation of target genes
50
How does contact inhibition work
B catenin is sequestered at junctions Cannot act in Wnt signalling Suppresses growth and differentiation
51
Cadherins activity in mesenchymal epithelial transition
Part of embryogenesis E cadherins switched off, allows cells to dissociate from epithelial layer Seen in gastrulation Cancer cells over express snail and slug with reduced cadherins Loss of cadherins increases available B catenin to increase Wnt
52
A catenin as a mechanosensor
Force unfolds the D3a, D3b and D4 domains Exposes vinculin and alpha actinin sites in D3a Stabilises junctions under force Unfolding at 5pN
53
Desmosomes
Link to keratin filaments Specific cadherins- desmoglein and desmocollin Plakoglobin and plakophillins intact with cadherins Bind the cadherins to desmoplakin that binds to keratin
54
Gastrulation
Vegetal pore of the blastula flattens Movement of cells upwards forming a blastopore and archenteron. Other cells break free to become a primary mesechyme More cells break free above the archenteron forming filopodia connections between the ectoderm and the archenteron The filopodia contract, extending the archenteron This causes the archenteron to have the endoderm cells that surround the archenteron and the blastopore forms the anus

Cell signalling (5 decks)

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